COVID-19-induced “acute respiratory distress syndrome” (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

COVID-19引起的“急性呼吸窘迫综合征”（ARDS）与长期呼吸衰竭和高死亡率相关，但肺损伤的机制基础仍不完全清楚。在这里，我们使用功能单细胞基因组学、免疫组织学和电子显微镜分析了两组 COVID-19 ARDS 患者的肺部免疫反应和肺部病理学。我们描述了表达 CD163 的单核细胞衍生巨噬细胞的积累，这些巨噬细胞在 COVID-19 ARDS 期间获得了促纤维化转录表型。基因集富集和计算数据整合揭示了 COVID-19 相关巨噬细胞与特发性肺纤维化中发现的促纤维化巨噬细胞群之间的显着相似性。 COVID-19 ARDS 与肺纤维化的临床、放射学、组织病理学和超微结构特征相关。将人类单核细胞暴露于 SARS-CoV-2，而不是甲型流感病毒或病毒 RNA 类似物，足以在体外诱导类似的促纤维化表型。总之，我们证明 SARS-CoV-2 会引发促纤维化巨噬细胞反应和明显的纤维增殖性 ARDS。